Tetraacetyl ribonic acid and process of making it



Patented Oct. 15, 1946 PATENT OFFICE.

TETRAACETYL RIBONIC ACID AND PROCESS or MAKING IT I Max Tishler, Rahway,N. J., assignor to Merck & 00., Inc., Rahway, N. .L, a corporation ofNew Jersey No Drawing. Application May 21,1941.

Serial No. 394,505

2Claims (01. 260-488) This invention relates to tetraacetyl ribonic acidand a process of making it, and is a continuation-in-part of co-pendingapplication Sename. 325,182, filed March 21, 1940, Patent No. 2,261,608.

I have discovered that tetraacyl ribonamide may be obtained byacetylating ribonamide, tetraacyl ribonic acid may be obtained bytreating tetraacyl ribonamide with nitrous anhydride, and that tetraacylribonic acid chloride may be obtained by treating tetraacyl ribonic acidwith phosphorous pentachloride.

The latter compound may be reduced to tetraacetyl ribose which may thenbe used in the synthesis of riboflavin.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given byway of illustration and not of limitation.

Example I Fifteen grams of ribonamide are added to a mixture of 74 cc.of acetic anhydride and 75 cc. of dry pyridine. The suspension is warmedwith agitation until the solid dissolves. The solution is allowed tostand overnight at room temperature. The tetraacetyl ribonamide whichcrystallizes out of the reaction mixture is filtered off. Yield (firstcrop) =14]? g.; M. P. 124-5 C.

The filtrate is added with stirring to 200 cc. of ice water and allowedto stand in an ice bath for one hour. A second crop is filtered off, andwashed with water, followed by 95% alcohol and ether. Yield (secondcrop) :63 g.; M. P. 1235-1245 C.

The filtrate from the second crop is extracted with 4X50 cc. of CHC13.The CHCla extract is washed with dilute (5%) NaHCOa solution, and thenwith water. The CHCla solution is dried over NaaSOr, and evaporatedunder reduced pressure to dryness. The residue is washed with ether.Yield (third crop) =32 g. M. P, 123-1235 C. Total yield=24.2 g. or 80%of theory.

Example 11 Twenty-six grams of cadmium ribonate (prepared from calciumd-arabinate by epimerization) are dissolved in 150 cc. of water, byheating on a steam bath. While the mixture is being 2 heated to -70 0.,hydrogen sulfide is passed into the solution with stirring until afiltered test portion no longer reacts with hydrogen sulfide. Themixture is filtered and the cadmium sulfide washed with hot water. Thewashings and filtrates are combined and concentrated under reducedpressure to dryness. The residue is then heated at -90 C. under reducedpressure for one hour. The syrupy lactone on standing slowlycrystallizes but for subsequent operations, the syrup may be usedwithout any purification.

The syrupy lactone is dissolved in cc. of absolute alcohol by warming.The solution is then cooled to 5 C., and while stirring. a solutioncontaining two equivalents of ammonia and methyl alcohol is addeddropwise. The mixture immediately becomes turbid and the product beginsto separate very soon. As soon as the product begins to separate, therate of ammonia addition may be greatly increased. The mixture isallowed to stand at between 0 and 5 C. for two hours after all theammonia has been added, is then filtered, and the d-ribonamide washedwith cold methyl alcohol. Yield, 16.5 to 17.5 g., M. P. 138139 C., withdecomposition. An additional small crop of product may be obtained byconcentrating the mother liquor under reduced pressure. Methyl alcoholmay also be used as a solvent with no difierence in yield.

A mixture of 10 g. of d-ribonamide, 38 cc. of acetic anhydride and 50cc. of dry pyridine is heated on a steam bath until solution occurs, andthen for an additional 15 minutes. The solution is then allowed to standfor A hour at room temperature. Ice is added together with seeds of theacetylated amide. After filtering off the crystalline material, themother liquor is extracted with chloroform, washed, dried, andconcentrated. The residue is taken up in ether and diluted withpetroleum ether whereby an additional yield of product separates. Thetetraacetyl d-ribonamide may be purified by recrystallization frommethyl alcohol and melts at 125-6 C. Yield 82%.

Alternatively, a mixture of 200 g. of d-ribonamide, g. of fused zincchloride, and 1200 cc. of acetic anhydride is stirred at 5 C. for twohours. During this time the ribonamide dissolves. The mixture is thenplaced in the cold room at about 3 C. for ten hours. The solution,

Example III Ten grams of tetraacetyl ribonamide in 40 cc. of glacialacetic acid are treated with N203 at 8-10 C. until the evolution of N2ceases. After the reaction mixture has stood overnight in therefrigerator (O-5 C.) it is added to a mixture of 175 cc. of water and'75 g. of NaHCOa. The alkaline solution is made acid to congo bytheaddition of dilute HCl (1-1), and warmed on the steam bath to 40 C. Theacidic solution is cooled and extracted with CHC13. The CHC13 extract is,dried over Na2SO4, and evaporated under reduced "pressure. (94.5% oftheory) M. P. 1313 C. Upon recrystallization from dry toluene, it meltsat 136-8 C.

The product may also be isolated after treatment with nitrous anhydrideby concentrating the acetic acid solution under dryness toa syrup. Thesyrup is then taken up in a little ether, and

Yield' of tetraacetyl ribonic acid=9.45 g.

4 allowed to crystallize. About 88% yield is ob tained by thisprocedure.

Example IV Ten grams of tetracetyl ribonic acid is suspended in 100 cc.of dry benzene, and 15-20 cc. of the benzene is distilled 01f to removeany residual water. The suspension is allowed to cool to roomtemperature, and 6.85 g. of PC15 are added. The reaction mixture isallowed to stand 24 hours with occasional shaking. The small amount ofsuspended matter is filtered off, and the solution evaporated underreduced pressure to dryness at a bath temperature of 50-60" C. The crudetetraacetyl ribonyl chloride is recrystallized from a mixture ofether-petroleum ether.

Yield=6.9 g. (73% theory); M. P. YO-71 C.

Other acyl derivatives may be obtained by employing different aliphaticor aromatic acids or

